Defense against Ancient Virus Opened Door to HIV

TOM HOPE AND DAVE MCDONALD/NORTHWESTERN UNIVERSITY
Early humans successfully fended off a virus that infected chimpanzees by evolving a protein capable of neutralizing it, according to a new study. But what goes around comes around, evolutionarily speaking: Four million years later, the same protein seems to have left us more vulnerable than other primates to the human immunodeficiency virus (HIV).

When researchers sequenced the chimpanzee genome in 2005, the biggest difference between it and the human genome was the extinct PtERV1 retrovirus, which inserted its DNA into the cells it infected like HIV does today. Chimps had 130 copies of PtERV1, but humans had none. "The question is: Why did our sister species get infected and not humans?" says virologist Michael Emerman of the Fred Hutchinson Cancer Research Center in Seattle.

Looking for an answer, Emerman and colleagues homed in on the immune protein TRIM5α, one of several proteins involved in innate immunity, the body's first line of defense against viral infection. The TRIM5α gene varies widely among primates and has changed the most between chimps and humans, suggesting that it evolved to combat some virus humans were susceptible to, Emerman says.

Rhesus monkey TRIM5α protects against HIV-1, but the only modern virus that the human protein has any effect on is one that causes leukemia in mice—which happens to be closely related to PtERV1. TRIM5α seems to neutralize the mouse virus's inner core protein after it has entered a cell. So Emerman and colleagues resurrected the analogous protein from PtERV1, based on its remnants in chimpanzees, and inserted it into a defective version of the mouse virus, which could infect cells but not reproduce.

The altered virus was unable to infect feline cells engineered to produce human TRIM5α, the group reports online today in Science. Unexpectedly, however, the researchers found that no version of TRIM5α from any primate could neutralize both PtERV1 and HIV—it was either one or the other, Emerman says. What that implies, he says, is "humans are susceptible to HIV today because of a response to something else we had in the past."

HIV researcher Beatrice Hahn of the University of Alabama at Birmingham calls the study a "fabulous piece of molecular sleuthing" and says that understanding innate immune proteins may eventually lead to new HIV treatment strategies.

TRIM5α is not the final word on HIV susceptibility, she adds. None of the proteins protect against HIV-2, which came to us from apes like HIV-1 did, she says, but humans have apparently fended off nearly 40 other monkey retroviruses, so our innate immunity "wasn't quite as bad as you thought."